It is well known that excitatory neurotransmission in the mammalian central nervous system is primarily mediated by the amino acid, L-glutamate, acting on ionotropic and metabotropic receptors. Glutamate can act at three types of ionotropic glutamate receptors, (R,S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl) propanoate (AMPA), kainate (KA) and N-methyl-D-aspartate (NMDA) receptors (Hollman and Heinemann, 1994, Annu. Rev. Neurosci. 17; 31-108). Molecular biological studies have established that AMPA receptors are composed of subunits (GluR 1-4) that can assemble to form functional channels. Five kainate receptors, classified as either high affinity (KA1 and KA2) or low affinity (Glur5, GluR6, and GluR7) kainate receptors have been identified (Bleakman et al., 1996, Mol. Pharmacol. 49, No. 4; 581-585).
It is well established that the hippocampus is important in learning and memory (Squire, 1992, Psychol. Rev. 99; 195-231) and it is considered that such cognitive functions are mediated by plastic changes in glutamatergic transmission within the hippocampus involving AMPA, NMDA and metabotropic receptor activation (Bliss and Collingridge, 1993, Nature, 361, 31-39). An example of such a plastic change is long term potentiation which can be demonstrated using standard electrophysiological methods in vivo, and in vitro, in hippocampal slices. Recently, it has been reported that kainate modulates neurotransmitter release in the hippocampus (Chittajullu et al., 1995, Nature 379, 78-81), but it remains unclear which receptors underlie this modulating effect of kainate.
We have presently discovered that compounds having activity at one of the kainate receptor subtypes, namely GluR5, modulate synaptic transmission within the hippocampus. Such compounds thus have potential for altering cognitive functions and are therefore indicated for the treatment of cognitive disorders.
One such compound having activity at the GluR5 receptor is ATPA (2-amino-3-(3-hydroxy-5-tert-butylisoxazol-4-yl)propanoic acid). ATPA is a known compound (Lauridsen et al., 1985; J. Med. Chem. 28: 668-672) and was hitherto regarded as a selective AMPA receptor agonist (Krogsgaard-Larsen et al.,1996, Eur.J. Med. Chem. 31: 515-537). We have discovered that ATPA is a potent GluR5 ligand with nanomolar activity on human GluR5 in binding studies, and is more than 1000-fold less potent on other human AMPA and kainate receptors. Furthermore, in electrophysiological studies we have discovered that ATPA is a potent GluR5 agonist with micromolar activity on human GluR5 and rat DRG neurons and is 100-fold less potent on other human AMPA and kainate receptors.
It i s also well known that the hippocampus is involved in many other physiological and pathological functions (Kato, N. (ed) 1996, The Hippocampus: Functions and Clinical Relevance. Elsevier, Amsterdam). Importantly the hippocampus is involved in convulsive disorders (Dingledine et al., 1990 TIPS 11, 334-338) and is subject to neurodegeneration as a result of ischaemic, hypoxic, and hypoglycemic episodes (Meldrum and Garthwaite, 1990 TIPS 11; 379-387). It is also well known that GluR5 receptors are distributed in other parts of the brain (Bettler et al., 1990, Neuron 5; 583-595).
It is further known that kainate receptors are located on dorsal root fibers and dorsal root ganglion neurons. ATPA is a potent agonist on these neurons which conduct nociceptive information into the spinal cord.
Thus, the present invention relates to methods of treating psychiatric and neurological disorders by administration of a compound that modulates the GluR5 receptor. Further, the present invention relates to assays for the identification of compounds that modulate the GluR5 receptor.
The treatment of mammalian psychiatric and neurological disorders is hereby furthered.